RESUMEN
In search for prodrugs to address the issue of pH-dependent solubility and exposure associated with 1 (BMS-582949), a previously disclosed phase II clinical p38α MAP kinase inhibitor, a structurally novel clinical prodrug, 2 (BMS-751324), featuring a carbamoylmethylene linked promoiety containing hydroxyphenyl acetic acid (HPA) derived ester and phosphate functionalities, was identified. Prodrug 2 was not only stable but also water-soluble under both acidic and neutral conditions. It was effectively bioconverted into parent drug 1 in vivo by alkaline phosphatase and esterase in a stepwise manner, providing higher exposure of 1 compared to its direct administration, especially within higher dose ranges. In a rat LPS-induced TNFα pharmacodynamic model and a rat adjuvant arthritis model, 2 demonstrated similar efficacy to 1. Most importantly, it was shown in clinical studies that prodrug 2 was indeed effective in addressing the pH-dependent absorption issue associated with 1.
Asunto(s)
Organofosfatos/farmacología , Fenilacetatos/farmacología , Profármacos/química , Profármacos/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Administración Oral , Animales , Artritis Experimental/tratamiento farmacológico , Disponibilidad Biológica , Técnicas de Química Sintética , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos/métodos , Macaca fascicularis , Masculino , Proteína Quinasa 14 Activada por Mitógenos/antagonistas & inhibidores , Estructura Molecular , Organofosfatos/química , Fenilacetatos/química , Profármacos/farmacocinética , Inhibidores de Proteínas Quinasas/química , Ratas Endogámicas Lew , Ratas Sprague-Dawley , Solubilidad , Relación Estructura-ActividadRESUMEN
Modification of a phenolic lead structure based on lessons learned from increasing the potency of steroidal glucocorticoid agonists lead to the discovery of exceptionally potent, nonsteroidal, indazole GR agonists. SAR was developed to achieve good selectivity against other nuclear hormone receptors with the ultimate goal of achieving a dissociated GR agonist as measured by human in vitro assays. The specific interactions by which this class of compounds inhibits GR was elucidated by solving an X-ray co-crystal structure.
Asunto(s)
Amidas/química , Amidas/farmacología , Descubrimiento de Drogas , Receptores de Glucocorticoides/agonistas , Sitios de Unión , Cristalografía por Rayos X , Humanos , Indazoles/química , Indazoles/farmacología , Estructura Molecular , Unión Proteica/efectos de los fármacos , Esteroides/química , Esteroides/farmacología , Relación Estructura-ActividadRESUMEN
SAR was used to further develop an indazole class of non-steroidal glucocorticoid receptor agonists aided by a GR LBD (ligand-binding domain)-agonist co-crystal structure described in the accompanying paper. Progress towards discovering a dissociated GR agonist guided by human in vitro assays biased the optimization of this compound series towards partial agonists that possessed excellent selectivity against other nuclear hormone receptors.
Asunto(s)
Indazoles/síntesis química , Indazoles/farmacología , Receptores de Glucocorticoides/agonistas , Amidas/química , Amidas/farmacología , Humanos , Indazoles/química , Modelos Moleculares , Unión Proteica/efectos de los fármacos , Receptores de Glucocorticoides/química , Relación Estructura-Actividad , Sulfonamidas/química , Sulfonamidas/farmacología , Urea/química , Urea/farmacologíaRESUMEN
A novel series of p38 MAP kinase inhibitors with high selectivity for the p38α isoform over the other family members including the highly homologous p38ß isoform has been identified. X-ray co-crystallographic studies have revealed an unprecedented kinase binding mode in p38α for representative analogs, 5c and 9d, in which a Leu108/Met109 peptide flip occurs within the p38α hinge region. Based on these findings, a general strategy for the rational design of additional promising p38α isoform selective inhibitors by targeting this novel binding mode is proposed.
Asunto(s)
Proteína Quinasa 14 Activada por Mitógenos/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Sitios de Unión , Cristalografía por Rayos X , Humanos , Enlace de Hidrógeno , Proteína Quinasa 14 Activada por Mitógenos/metabolismo , Simulación de Dinámica Molecular , Unión Proteica , Isoformas de Proteínas/antagonistas & inhibidores , Isoformas de Proteínas/metabolismo , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/metabolismo , Estructura Terciaria de Proteína , Relación Estructura-ActividadRESUMEN
A series of carbamoylmethylene linked prodrugs of 1 (BMS-582949), a clinical p38α inhibitor, were synthesized and evaluated. Though the phosphoryloxymethylene carbamates (3, 4, and 5) and α-aminoacyloxymethylene carbamates (22, 23, and 26) were found unstable at neutral pH values, fumaric acid derived acyloxymethylene carbamates (2, 28, and 31) were highly stable under both acidic and neutral conditions. Prodrugs 2 and 31 were also highly soluble at both acidic and neutral pH values. At a solution dose of 14.2mpk (equivalent to 10mpk of 1), 2 gave essentially the same exposure of 1 compared to dosing 10mpk of 1 itself. At a suspension dose of 142mpk (equivalent to 100mpk of 1), 2 demonstrated that it could overcome the solubility issue associated with 1 and provide a much higher exposure of 1. To our knowledge, the unique type of prodrugs like 2, 28, and 31 was not reported in the past and could represent a novel prodrug approach for secondary amides, a class of molecules frequently identified as drug candidates.
Asunto(s)
Dacarbazina/análogos & derivados , Profármacos/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Pirroles/farmacología , Triazinas/farmacología , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidores , Animales , Cristalografía por Rayos X , Dacarbazina/química , Relación Dosis-Respuesta a Droga , Concentración de Iones de Hidrógeno , Modelos Moleculares , Estructura Molecular , Profármacos/administración & dosificación , Profármacos/síntesis química , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/síntesis química , Pirroles/administración & dosificación , Pirroles/síntesis química , Ratas , Solubilidad , Relación Estructura-Actividad , Temperatura , Triazinas/administración & dosificación , Triazinas/síntesis química , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
The synthesis, structure-activity relationships (SAR), and biological results of pyridyl-substituted azaindole based tricyclic inhibitors of IKK2 are described. Compound 4m demonstrated potent in vitro potency, acceptable pharmacokinetic and physicochemical properties, and efficacy when dosed orally in a mouse model of inflammatory bowel disease.
Asunto(s)
Acetamidas/química , Descubrimiento de Drogas , Inhibidores Enzimáticos/química , Compuestos Heterocíclicos con 3 Anillos/química , Quinasa I-kappa B/antagonistas & inhibidores , Acetamidas/síntesis química , Acetamidas/farmacología , Administración Oral , Animales , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Compuestos Heterocíclicos con 3 Anillos/síntesis química , Compuestos Heterocíclicos con 3 Anillos/farmacología , Humanos , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Concentración 50 Inhibidora , Ratones , Estructura Molecular , Ratas , Relación Estructura-ActividadRESUMEN
Structurally novel 5H-chromeno[2,3-b]pyridine (azaxanthene) selective glucocorticoid receptor (GR) modulators have been identified. A screening paradigm utilizing cellular assays of GR-mediated transrepression of proinflammatory transcription factors and transactivation of GR-dependent genes combined with three physiologically relevant assays of cytokine induction in human whole blood has allowed for the identification of high affinity, selective GR ligands that display a broad range of pharmacological profiles. Agonist efficacy in reporter assays can be tuned by halogenation of a pendent phenyl ring and correlates well with efficacy for cytokine inhibition in human whole blood. A hypothetical binding mode is proposed, invoking an expanded ligand binding pocket resembling that of arylpyrazole-bound GR structures. Two compounds of close structural similarity (35 and 37; BMS-776532 and BMS-791826, respectively) have been found to maintain distinct and consistent levels of partial agonist efficacy across several assays, displaying anti-inflammatory activity comparable to that of prednisolone 2 in suppressing cytokine production in whole blood and in rodent models of acute and chronic inflammation.
Asunto(s)
Antiinflamatorios no Esteroideos/síntesis química , Compuestos Heterocíclicos con 3 Anillos/síntesis química , Receptores de Glucocorticoides/agonistas , Tiadiazoles/síntesis química , Fosfatasa Alcalina/biosíntesis , Animales , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/farmacología , Artritis Experimental/tratamiento farmacológico , Línea Celular Tumoral , Agonismo Parcial de Drogas , Edema/tratamiento farmacológico , Glutamato-Amoníaco Ligasa/biosíntesis , Compuestos Heterocíclicos con 3 Anillos/química , Compuestos Heterocíclicos con 3 Anillos/farmacología , Humanos , Técnicas In Vitro , Interleucina-1beta/sangre , Masculino , Modelos Moleculares , Ratas , Ratas Endogámicas Lew , Ratas Sprague-Dawley , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/metabolismo , Elementos de Respuesta , Estereoisomerismo , Relación Estructura-Actividad , Tiadiazoles/química , Tiadiazoles/farmacología , Factor de Transcripción AP-1/genética , Factor de Transcripción AP-1/metabolismo , Activación Transcripcional , Factor de Necrosis Tumoral alfa/sangre , Tirosina Transaminasa/biosíntesisRESUMEN
Pyrrolo[2,1-f][1,2,4]triazine based inhibitors of p38α have been prepared exploring functional group modifications at the C6 position. Incorporation of aryl and heteroaryl ketones at this position led to potent inhibitors with efficacy in in vivo models of acute and chronic inflammation.
Asunto(s)
Antiinflamatorios/química , Proteína Quinasa 14 Activada por Mitógenos/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Pirroles/química , Triazinas/química , Administración Oral , Animales , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Artritis/tratamiento farmacológico , Sitios de Unión , Cristalografía por Rayos X , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Femenino , Ratones , Proteína Quinasa 14 Activada por Mitógenos/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Estructura Terciaria de Proteína , Ratas , Relación Estructura-Actividad , Triazinas/farmacología , Triazinas/uso terapéuticoRESUMEN
The synthesis, structure-activity relationships (SAR) and biological evaluation of thiazole based tricyclic inhibitors of IKK2 are described. Compound 9 was determined to be orally efficacious in a murine model of rheumatoid arthritis.
Asunto(s)
Artritis Reumatoide/tratamiento farmacológico , Quinasa I-kappa B/antagonistas & inhibidores , Imidazoles/química , Inhibidores de Proteínas Quinasas/química , Piridinas/química , Tiazoles/química , Animales , Modelos Animales de Enfermedad , Perros , Evaluación Preclínica de Medicamentos , Femenino , Quinasa I-kappa B/metabolismo , Ratones , Ratones Endogámicos BALB C , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/uso terapéutico , Piridinas/farmacocinética , Piridinas/uso terapéutico , Ratas , Relación Estructura-ActividadRESUMEN
A series of 2,2-dimethyl-3,3-diphenyl-propanamides as novel glucocorticoid receptor modulators is reported. SAR exploration led to the identification of 4-hydroxyphenyl propanamide derivatives displaying good agonist activity in GR-mediated transrepression assays and reduced agonist activity in GR-mediated transactivation assays. Compounds 17 and 30 showed anti-inflammatory activity comparable to prednisolone in the rat carrageenan-induced paw edema model, with markedly decreased side effects with regard to increases in blood glucose and expression of hepatic tyrosine aminotransferase. A hypothetical binding mode accounting for the induction of the functional activity by a 4-hydroxyl group is proposed.
Asunto(s)
Amidas/farmacología , Receptores de Glucocorticoides/agonistas , Amidas/química , Animales , Modelos Moleculares , RatasRESUMEN
The synthesis and structure-activity relationships (SAR) of p38α MAP kinase inhibitors based on a 5-amino-pyrazole scaffold are described. These studies led to the identification of compound 2j as a potent and selective inhibitor of p38α MAP kinase with excellent cellular potency toward the inhibition of TNFα production. Compound 2j was highly efficacious in vivo in inhibiting TNFα production in an acute murine model of TNFα production. X-ray co-crystallography of a 5-amino-pyrazole analog 2f bound to unphosphorylated p38α is also disclosed.
Asunto(s)
Proteína Quinasa 14 Activada por Mitógenos/química , Inhibidores de Proteínas Quinasas/síntesis química , Pirazoles/farmacología , Animales , Cristalografía por Rayos X , Ratones , Proteína Quinasa 14 Activada por Mitógenos/antagonistas & inhibidores , Unión Proteica , Conformación Proteica , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Pirazoles/síntesis química , Pirazoles/química , Relación Estructura-Actividad , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/biosíntesisRESUMEN
The discovery and characterization of 7k (BMS-582949), a highly selective p38α MAP kinase inhibitor that is currently in phase II clinical trials for the treatment of rheumatoid arthritis, is described. A key to the discovery was the rational substitution of N-cyclopropyl for N-methoxy in 1a, a previously reported clinical candidate p38α inhibitor. Unlike alkyl and other cycloalkyls, the sp(2) character of the cyclopropyl group can confer improved H-bonding characteristics to the directly substituted amide NH. Inhibitor 7k is slightly less active than 1a in the p38α enzymatic assay but displays a superior pharmacokinetic profile and, as such, was more effective in both the acute murine model of inflammation and pseudoestablished rat AA model. The binding mode of 7k with p38α was confirmed by X-ray crystallographic analysis.
Asunto(s)
Antiinflamatorios no Esteroideos/síntesis química , Proteína Quinasa 14 Activada por Mitógenos/antagonistas & inhibidores , Pirroles/síntesis química , Triazinas/síntesis química , Animales , Antiinflamatorios no Esteroideos/farmacocinética , Antiinflamatorios no Esteroideos/farmacología , Artritis Experimental/tratamiento farmacológico , Artritis Reumatoide/tratamiento farmacológico , Disponibilidad Biológica , Células CACO-2 , Cristalografía por Rayos X , Femenino , Humanos , Enlace de Hidrógeno , Técnicas In Vitro , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Lipopolisacáridos/farmacología , Masculino , Ratones , Ratones Endogámicos BALB C , Microsomas Hepáticos/metabolismo , Proteína Quinasa 14 Activada por Mitógenos/química , Modelos Moleculares , Conformación Molecular , Unión Proteica , Pirroles/farmacocinética , Pirroles/farmacología , Ratas , Ratas Endogámicas Lew , Ratas Sprague-Dawley , Estereoisomerismo , Relación Estructura-Actividad , Triazinas/farmacocinética , Triazinas/farmacología , Factor de Necrosis Tumoral alfa/biosíntesisRESUMEN
The design, synthesis, and structure-activity relationships (SAR) of a series of 2-aminothiazol-5-yl-pyrimidines as novel p38α MAP kinase inhibitors are described. These efforts led to the identification of 41 as a potent p38α inhibitor that utilizes a unique nitrogen-sulfur intramolecular nonbonding interaction to stabilize the conformation required for binding to the p38α active site. X-ray crystallographic studies that confirm the proposed binding mode of this class of inhibitors in p38 α and provide evidence for the proposed intramolecular nitrogen-sulfur interaction are discussed.
Asunto(s)
Proteína Quinasa 14 Activada por Mitógenos/antagonistas & inhibidores , Nitrógeno/química , Inhibidores de Proteínas Quinasas/síntesis química , Pirimidinas/química , Azufre/química , Tiazoles/química , Sitios de Unión , Cristalografía por Rayos X , Diseño de Fármacos , Proteína Quinasa 14 Activada por Mitógenos/metabolismo , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Estructura Terciaria de Proteína , Pirimidinas/síntesis química , Pirimidinas/farmacología , Relación Estructura-Actividad , Tiazoles/síntesis química , Tiazoles/farmacologíaRESUMEN
The first stereoselective synthesis of the hexahydroimidazo[1,5b]isoquinoline (HHII) scaffold as a surrogate for the steroidal A-B ring system is described. The structure-activity relationships of the analogs derived from this scaffold show that the basic imidazole moiety is tolerated by the glucocorticoid receptor (GR) in terms of binding affinity, although the partial agonist activity in the transrepressive assays depends on the substitution pattern on the B-ring. More importantly, most compounds in the HHII series bearing a tertiary alcohol moiety on the B-ring are either inactive or significantly less active in inducing GR-mediated transactivation, thus displaying a "dissociated" pharmacology in vitro.
Asunto(s)
Isoquinolinas/síntesis química , Isoquinolinas/farmacología , Receptores de Glucocorticoides/agonistas , Dexametasona/farmacología , Selectina E/genética , Selectina E/metabolismo , Genes Reporteros , Células HeLa , Humanos , Isoquinolinas/química , Pulmón/citología , Pulmón/efectos de los fármacos , Estructura Molecular , Regiones Promotoras Genéticas , Relación Estructura-Actividad , Transcripción Genética , Activación TranscripcionalRESUMEN
A new series of tricyclic-based inhibitors of IKK have been derived from an earlier lead compound. The synthesis and structure-activity relationships (SAR) are described. Compound 4k inhibited TNF production in rats stimulated with LPS.
Asunto(s)
Quinasa I-kappa B/antagonistas & inhibidores , Imidazoles/síntesis química , Inhibidores de Proteínas Quinasas/síntesis química , Pirimidinas/síntesis química , Animales , Quinasa I-kappa B/metabolismo , Imidazoles/química , Imidazoles/farmacología , Lipopolisacáridos/farmacología , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/química , Pirimidinas/farmacología , Ratas , Relación Estructura-Actividad , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
The design and synthesis of a novel series of oxazole-, thiazole-, and imidazole-based inhibitors of IkappaB kinase (IKK) are reported. Biological activity was improved compared to the pyrazolopurine lead, and the expedient synthesis of the new tricyclic systems allowed for efficient exploration of structure-activity relationships. This, combined with an iterative rat cassette dosing strategy, was used to identify compounds with improved pharmacokinetic (PK) profiles to advance for in vivo evaluation.
Asunto(s)
Compuestos Heterocíclicos con 3 Anillos/síntesis química , Quinasa I-kappa B/antagonistas & inhibidores , Imidazoles/síntesis química , Oxazoles/síntesis química , Tiazoles/síntesis química , Animales , Cristalografía por Rayos X , Femenino , Glutatión Transferasa/genética , Glutatión Transferasa/metabolismo , Compuestos Heterocíclicos con 3 Anillos/farmacocinética , Compuestos Heterocíclicos con 3 Anillos/farmacología , Humanos , Quinasa I-kappa B/genética , Imidazoles/farmacocinética , Imidazoles/farmacología , Técnicas In Vitro , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/metabolismo , Lipopolisacáridos/farmacología , Ratones , Ratones Endogámicos BALB C , Microsomas Hepáticos/metabolismo , Oxazoles/farmacocinética , Oxazoles/farmacología , Ratas , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/metabolismo , Relación Estructura-Actividad , Tiazoles/farmacocinética , Tiazoles/farmacología , Factor de Necrosis Tumoral alfa/biosíntesisRESUMEN
The synthesis and structure-activity relationships (SAR) of p38 alpha MAP kinase inhibitors based on a pyrazolo-pyrimidine scaffold are described. These studies led to the identification of compound 2x as a potent and selective inhibitor of p38 alpha MAP kinase with excellent cellular potency toward the inhibition of TNFalpha production. Compound 2x was highly efficacious in vivo in inhibiting TNFalpha production in an acute murine model of TNFalpha production. X-ray co-crystallography of a pyrazolo-pyrimidine analog 2b bound to unphosphorylated p38 alpha is also disclosed.
Asunto(s)
Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Pirazoles/química , Pirimidinas/síntesis química , Pirimidinas/farmacología , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidores , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Cristalografía por Rayos X , Humanos , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteínas Quinasas/química , Pirimidinas/química , Relación Estructura-Actividad , Proteínas Quinasas p38 Activadas por Mitógenos/químicaRESUMEN
Rational design, synthesis, and SAR studies of a novel class of benzothiazole based inhibitors of p38alpha MAP kinase are described. The issue of metabolic instability associated with vicinal phenyl, benzo[d]thiazol-6-yl oxazoles/imidazoles was addressed by the replacement of the central oxazole or imidazole ring with an aminopyrazole system. The proposed binding mode of this new class of p38alpha inhibitors was confirmed by X-ray crystallographic studies of a representative inhibitor (6a) bound to the p38alpha enzyme.
Asunto(s)
Benzotiazoles/química , Proteína Quinasa 14 Activada por Mitógenos/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Animales , Células Cultivadas/efectos de los fármacos , Células Cultivadas/enzimología , Cristalografía por Rayos X , Humanos , Lipopolisacáridos/farmacología , Ratones , Microsomas/efectos de los fármacos , Microsomas/enzimología , Proteína Quinasa 14 Activada por Mitógenos/metabolismo , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacocinética , Ratas , Relación Estructura-Actividad , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
The synthesis and structure-activity relationships (SAR) of p38alpha MAP kinase inhibitors based on heterobicyclic scaffolds are described. This effort led to the identification of compound (21) as a potent inhibitor of p38alpha MAP kinase with good cellular potency toward the inhibition of TNF-alpha production. X-ray co-crystallography of an oxalamide analog (24) bound to unphosphorylated p38alpha is also disclosed.
Asunto(s)
Compuestos Bicíclicos con Puentes/síntesis química , Compuestos Bicíclicos con Puentes/farmacología , Compuestos Heterocíclicos/síntesis química , Compuestos Heterocíclicos/farmacología , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidores , Compuestos Bicíclicos con Puentes/química , Cristalografía por Rayos X , Compuestos Heterocíclicos/química , Modelos Moleculares , Inhibidores de Proteínas Quinasas/química , Relación Estructura-ActividadRESUMEN
A series of structurally novel aminothiazole based small molecule inhibitors of Itk were prepared to elucidate their structure-activity relationships (SARs), selectivity, and cell activity in inhibiting IL-2 secretion in a Jurkat T-cell assay. Compound 3 is identified as a potent and selective Itk inhibitor which inhibits anti-TCR antibody induced IL-2 production in mice in vivo and was previously reported to reduce lung inflammation in a mouse model of ovalbumin induced allergy/asthma.